Relationship between insult intensity and mode of hair cell loss in the vestibular system of rats exposed to 3,3'-iminodipropionitrile.

Abstract

A variety of stimuli cause sensory hair cell loss in the mammalian inner ear. This loss occurs by several differing processes, the significance of which remains undetermined. This study examines the relationship between the intensity of the damaging stimulus and the mode of hair cell loss found in the vestibular sensory epithelia of the rat. The ototoxin 3,3'-iminodipropionitrile (IDPN) was administered to rats at three different intoxication rates: acute exposure to high doses, repeated exposure to intermediate doses, and subchronic exposure to low doses. The morphology of the vestibular epithelia was examined by light microscopy and by scanning and transmission electron microscopy (SEM and TEM). In addition, DNA fragmentation in the epithelia was assessed by terminal deoxynucleotidyl transferase (tdt)-dUTP-nick-end-label (TUNEL). One day after acute IDPN, necrosis of hair cells was observed. However, at day 4 with this dose, and 1 and 4 days after repeated exposure, apoptotic figures and positive TUNEL labeling predominated. Subchronic IDPN resulted in a slowly evolving extrusion of basically intact hair cells in the crista and utricle. The data demonstrate that extrusion is a major mechanism of hair cell demise in mammals, that necrosis, apoptosis, and extrusion form a continuum of modes of hair cell loss, and that the intensity of the damaging stimulus determines the prevalence of each mode: Necrosis was most evident when the intensity was at its highest, whereas extrusion predominated when the intensity was at the lowest end of the scale.